This invention is related to a composition for protecting brain cells and improving memory comprising Asiasari Radix extracts.
One of the major factors involved in brain cell damages is glutamate. Glutamate exerts its actions by binding to four types of receptors including NMDA receptor, AMPA receptor, Kainate receptor and 1S,3R-ACPD receptor (Craig CR, Stitzel RE, Modern Pharmacology with clinical applications, 293–302, 1997). When brain ischemia occurs, oxygen supply to brain cells diminishes and then anaerobic glycolysis increases. Therefore, ATP content in the cell decreases and the concentration of extracellular potassium ions increases. Eventually, depolarization of neuronal cell membrane and subsequent release of excitatory amino acids occurs which results in the neuronal damages by the activation of receptors for NMDA, AMPA and Kainate. Excitotoxicity via excitatory neurotransmitters induces cellular stress and thereby plays an important role in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease, Parkinson disease, strokes and amyotrophic lateral sclerosis [Haloween, B., J. Neurochem. 59, 1609–1623, 1992; Coyle, J. T. and Puttfarcken, P., Science 262, 689–695. 1993; Olanow, C. W., Trends. Neurosci. 16, 439–444, 1993].
Neurodegenerative disorders in the central nervous system are often accompanied by a decrease in cognition and memory. Especially, dementia is a serious problem of modern societies with high population of elderly. Dementia is typically caused by a variety of environmental factors such as genetics, aging, brain damage, smoking and alcohol and other complex factors. The hippocampus of patients suffering from dementia is heavily damaged and this is closely related to the reduction of acetylcholine levels in the brain.
Acetylcholinesterase inhibitors are clinically used for the Alzheimer's disease to increase acetylcholine levels. Recently, a great number of researches have been performed to search for ways of neuroprotection such as by using NMDA antagonist, AMPA antagonist, GABA agonist, intracellular calcium decreasing agent, nitric oxide inhibitor, free radical scavenger, Na channel blocker, inhibitor of glutamate release, acidosis, hypothermia and potassium channel activator [Gagliardi RJ, Neuroprotection, excitatotoxicity and NMDA antagonists, Arq. Neuro-Psiquiatr. 58, 2000].
Dozocyilpin (MK 801), selfotel, cerestat, and dextrometorfan have been developed as NMDA antagonists. However, they are known to induce altered sensory perception, dysphoria, nystagmus, and hypotension at low doses, while inducing psychological adverse events such as excitement, paranoia, and hallucination at higher doses. Furthermore, NBQX was developed as an AMPA antagonist. However, it causes severe kidney toxicity and is thus not optimal in clinical applications. Therefore, neuroprotective agents without toxicity from natural product-derived materials need to be developed.
Recently, it has been found that AMPA receptor plays an important role in the development of Alzheimer's disease. The fact that neuronal cell damages by the AMPA receptor activation occurs selectively at the basal forebrain cholinergic neurons (BFCNs) suggests that development of anti-Alzheimer's disease can be tried by using AMPA receptor antagonists [Weiss, J. H., et al., Basal forebrain cholinergic neurons are selectively vulnerable to AMPA/kainate receptor-mediated neurotoxicity. Neuroscience 60, 659–664, 1994].
Glial cells are essential for the survival of neuronal cells. In developing the central nervous system, glial cells control the precise movement and growth of neuronal cells whereas they play a role in homeostasis and synaptic plasticity of neuronal cells after development. In addition, glial cells contain receptors and neurotransmitters capable of initiating neuronal signal transduction essential for survival and apoptosis of neuronal cells. Thus, protecting glial cells from external damages are eventually related to the plasticity, homeostasis and survival of neuronal cells.
Insulin receptor in the peripheral tissues participates mainly in the glucose metabolism whereas its role in the CNS appeared not to be related to glucose metabolism but other neuronal activity such as memory. In fact, insulin receptor is widely distributed in different areas in the brain and present in a large amount in the hippocampus. Hence, the hippocampus is an important target of insulin action in the brain. Recently, much evidence has been presented as to the role of brain insulin or insulin receptors in the memory formation. It has been found that both experimental damage to the neuronal insulin receptor and Alzheimer brain induced similar metabolic abnormalities [Hoyer, S., Muller, D, Plaschke, K. Desensitization of brain insulin receptor. Effect on glucose/energy and related metabolism. J. Neural Transm [Suppl] 44, 259–268, 1994].
Interesting hypothesis has been proposed that sporadic Alzheimer disease might be the brain type of non-insulin dependent diabetes mellitus (Hoyer, S. Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis. J. Neural Transm. 105, 415–422, 1998). It has been suggested that intracerebroventricular insulin enhances memory in a passive-avoidance task [Park, C. P., Seeley, R. J., Craft, S. and Woods S. C. (2000) Intracerebroventricular insulin enhances memory in a passive avoidance task. Physiol. Behav. 68, 509–514]. Insulin receptor density and tyrosine kinase activity in the sporadic Alzheimer's disease (SAD) or sporadic dementia of Alzheimer's type (SDAT) were known to be significantly decreased [Frolich, L., Blum-degen, D., Bernstein, H. G., Engelsberger, S., Humrich, J., Laufer, S., Muschner, D., Thalheimer, A., Turk, A., Hoyer, S., Zochling, R., Boissl, K. W., Jellinger, K., and Piederer, P. Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease. J. Neural Transm. 105, 423–438, 1998]. Interestingly, tyrosine phosphorylation of the hippocampal insulin receptor has been shown to play an essential role in spatial memory formation [Zhao, W., Chen, H., Xu, H., Moore, E., Meiri, N., Quon, M. J., Alkon, D. L. (1999) Brain insulin receptors and spatial memory. J. Biol. Chem. 274, 34893–34902, 1999].